The present invention relates to therapeutics for the prevention and treatment of inflammatory bowel disease, and in particular the prevention and treatment of inflammatory bowel disease in humans as well as other animals through the use of biologically active vitamin D compounds.
Inflammatory bowel diseases (IBD) are defined by chronic, relapsing intestinal inflammation of obscure origin. IBD refers to two distinct disorders, Crohn""s disease and ulcerative colitis (UC). Both diseases appear to involve either a dysregulated immune response to GI tract antigens, a mucosal barrier breach, and/or an adverse inflammatory reaction to a persistent intestinal infection. The GI tract luminal contents and bacteria constantly stimulate the mucosal immune system, and a delicate balance of proinflammatory and anti-inflammatory cells and molecules maintains the integrity of the GI tract, without eliciting severe and damaging inflammation [MacDermott, R. P., J Gastroenterology, 31:907:-916 (1996)]. It is unknown how the IBD inflammatory cascade begins, but constant GI antigen-dependent stimulation of the mucosal and systemic immune systems perpetuates the inflammatory cascade and drives lesion formation.
There is no known cure for IBD, which afflicts 2 million Americans. Current methods of managing IBD symptoms cost an estimated $1.2 billion annually in the United States alone.
In patients with IBD, ulcers and inflammation of the inner lining of the intestines lead to symptoms of abdominal pain, diarrhea, and rectal bleeding. Ulcerative colitis occurs in the large intestine, while in Crohn""s, the disease can involve the entire GI tract as well as the small and large intestines. For most patients, IBD is a chronic condition with symptoms lasting for months to years. It is most common in young adults, but can occur at any age. It is found worldwide, but is most common in industrialized countries such as the United States, England, and northern Europe. It is especially common in people of Jewish descent and has racial differences in incidence as well. The clinical symptoms of IBD are intermittent rectal bleeding, crampy abdominal pain, weight loss and diarrhea. Diagnosis of IBD is based on the clinical symptoms, the use of a barium enema, but direct visualization (sigmoidoscopy or colonoscopy) is the most accurate test. Protracted IBD is a risk factor for colon cancer. The risk for cancer begins to rise significantly after eight to ten years of IBD.
Some patients with UC only have disease in the rectum (proctitis). Others with UC have disease limited to the rectum and the adjacent left colon (proctosigmoiditis). Yet others have UC of the entire colon (universal IBD). Symptoms of UC are generally more severe with more extensive disease (larger portion of the colon involved with disease).
The prognosis for patients with disease limited to the rectum (proctitis) or UC limited to the end of the left colon (proctosigmoiditis) is better then that of full colon UC. Brief periodic treatments using oral medications or enemas may be sufficient. In those with more extensive disease, blood loss from the inflamed intestines can lead to anemia, and may require treatment with iron supplements or even blood transfusions. Rarely, the colon can acutely dilate to a large size when the inflammation becomes very severe. This condition is called toxic megacolon. Patients with toxic megacolon are extremely ill with fever, abdominal pain and distention, dehydration, and malnutrition. Unless the patient improves rapidly with medication, surgery is usually necessary to prevent colon rupture.
Crohn""s disease can occur in all regions of the gastrointestinal tract. With this disease intestinal obstruction due to inflammation and fibrosis occurs in a large number of patients. Granulomas and fistula formation are frequent complications of Crohn""s disease. Disease progression consequences include intravenous feeding, surgery and colostomy.
The most commonly used medications to treat IBD are anti-inflammatory drugs such as the salicylates. The salicylate preparations have been effective in treating mild to moderate disease. They can also decrease the frequency of disease flares when the medications are taken on a prolonged basis. Examples of salicylates include sulfasalazine, olsalazine, and mesalamine. All of these medications are given orally in high doses for maximal therapeutic benefit. These medicines are not without side effects. Azulfidine can cause upset stomach when taken in high doses, and rare cases of mild kidney inflammation have been reported with some salicylate preparations.
Corticosteroids are more potent and faster-acting than salicylates in the treatment of IBD, but potentially serious side effects limit the use of corticosteroids to patients with more severe disease. Side effects of corticosteroids usually occur with long term use. They include thinning of the bone and skin, infections, diabetes, muscle wasting, rounding of faces, psychiatric disturbances, and, on rare occasions, destruction of hip joints.
In IBD patients that do not respond to salicylates or corticosteroids, medications that suppress the immune system are used. Examples of immunosuppressants include azathioprine and 6-mercaptopurine. Immunosuppressants used in this situation help to control IBD and allow gradual reduction or elimination of corticosteroids. However, immunosuppressants cause increased risk of infection, renal insufficiency, and the need for hospitalization.
Clearly there is a great need for agents capable of preventing and treating IBD. It would be desirable if such agents could be administered in a cost-effective and timely fashion, with a minimum of adverse side effects.
The phrase xe2x80x9cvitamin D compoundsxe2x80x9d include, but are not limited to compounds which have at least one of the following features: the C-ring, D-ring and 3xcex2-hydroxycyclohexane A-ring of vitamin D interconnected by the 5,7 diene double bond system of vitamin D together with any side chain attached to the D-ring (i.e. compounds with a xe2x80x98vitamin D nucleusxe2x80x99 and substituted or unsubstituted A-, C-, and D-rings interconnected by a 5,7 diene double bond system typical of vitamin D together with a side chain attached to the D-ring).
The phrase xe2x80x9cnonsecosteroidal vitamin D mimicsxe2x80x9d is defined as nonsecosteroid compounds which are capable of mimicking various activities of the secosteroid calcitriol. Examples of such compounds include, but are not limited to, LG190090, LG190119, LG190155, LG190176, and LG1900178 [See, Boehm et al., Chemistry and Biology 6:265-275 (1999)].
The phrase xe2x80x9cbiologically active vitamin D compoundxe2x80x9d is defined as encompassing vitamin D compounds and nonsecosteroidal vitamin D mimics which are biologically active in vivo, or are acted upon in a subject (i.e. host) such that the compound becomes active in vivo. Examples of such compounds include, but are not limited to: vitamin D, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) [a.k.a. calcitriol], and analogs thereof [e.g. 1xcex1-hydroxyvitamin D3 (1xcex1-OH-D3), 1,25-dihydroxyvitamin D2 (1,25-(OH)2D2), 1xcex1-hydroxyvitamin D2 (1xcex1-OH-D2), 1xcex1,25-(OH)2-16-ene-D3, 1xcex1,25-(OH)2-24-oxo-16-ene-D3, 1xcex1,24R(OH)2-D3, 1xcex1,25(OH)2-22-oxa-D3, 20-epi-22-oxa-24a,24b,-dihomo-1xcex1,25(OH)2-D3, 20-epi-22-oxa-24a,26a,27a,-trihomo-1xcex1,25 (OH)2-D3, 20-epi-22-oxa-24homo-1xcex1,25(OH)2-D3, 1,25-(OH)2-16,23E-diene-26-trifluoro-19-nor-D3, and nonsecosteroidal vitamin D mimics. Further examples are provided below, including various structural formulas, detailed in part III.
The phrase xe2x80x9csymptoms of IBDxe2x80x9d is herein defined to include symptoms, including, but not limited to, abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g. weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g. anemia) or a test that detects the presence of blood (e.g. rectal bleeding).
The phrase xe2x80x9ccalcemic responsexe2x80x9d is herein defined as the biological response caused by many biologically active vitamin D compounds (e.g. calcitriol) when administered to a subject. The response includes, but is not limited to, elevated calcium concentrations in serum, increased intestinal absorption of dietary calcium, increased urinary calcium excretion, and increased bone calcium mobilization.
The phrase xe2x80x9csymptoms of hypercalcemiaxe2x80x9d is herein defined to detected symptoms including, but not limited to, calcium deposition in the kidneys (nephrocalcinosis), kidney stones (nephrolithiasis), uremia, manifestations of muscle weakness, lethargy, coma, constipation, anorexia, nausea, vomiting, shortening of the QT interval, hypotension, and arrhythmias.
The phrase xe2x80x9cserious hypercalcemiaxe2x80x9d is herein defined as the condition where a subject is suffering from symptoms of hypercalcemia which require immediate medical attention to prevent life threatening illness or death. Examples include, but are not limited to, nephrocalcinosis, nephrolithiasis, uremia, coma, and anorexia.
The phrase xe2x80x9cmild hypercalcemiaxe2x80x9d is herein defined as the condition where a subject is suffering from symptoms of hypercalcemia which do not require immediate medical attention to prevent life threatening illness or death. Examples include, but are not limited to, manifestations of muscle weakness, lethargy, constipation, nausea, vomiting, shortening of the QT interval, hypotension, and arrhythmia.
The phrase xe2x80x9ca therapeutically effective amountxe2x80x9d of a biologically active vitamin D compound is herein defined as the dosage level required for a patient such that the symptoms of IBD are reduced.
The phrase xe2x80x9cunder conditions such that the symptoms are reducedxe2x80x9d refers to any degree of qualitative or quantitative reduction in detectable symptoms of IBD, including but not limited to, a detectable impact on the rate of recovery from disease (e.g. rate of weight gain), or the reduction of at least one of the following symptoms: abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, dehydration, anemia, distention, fibrosis, inflamed intestines and malnutrition.
The phrase xe2x80x9cat risk for IBDxe2x80x9d is herein defined as encompassing the segment of the world population that has an increased risk (i.e. over the average person) for IBD. IBD is most commonly found in young adults, but can occur at any age. It occurs worldwide, but is most common in the United States, England, and northern Europe. It is especially common in people of Jewish descent. An increased frequency of this condition has been recently observed in developing nations. Increased risk is also present in people with family members who suffer from inflammatory bowel disease.
The phrase xe2x80x9ctherapeutic composition comprising biologically active vitamin D compoundsxe2x80x9d refers to compositions containing the biologically active vitamin D compounds of the present invention, or the biologically active vitamin D compounds of the present invention provided together with one or more other compounds or agents including, but not limited to, other biologically active vitamin D compounds, physiologically tolerable liquids, gels, carriers, diluents, adjuvants, excipients, salicylates, steroids, immunosuppressants, antibodies, cytokines, antibiotics, binders, fillers, preservatives, stabilizing agents, emulsifiers, and buffers.
The phrase xe2x80x9ccontinuous mannerxe2x80x9d when used in reference to the method of delivery or administration of the biologically active vitamin D compounds of the present invention, is defined as meaning a substantially uninterrupted administration of the compounds of the present invention, such that a therapeutic dosage is stretched over a period of time and avoids a dosage xe2x80x98spikexe2x80x99 which is common among other modes of administration (e.g. oral administration or intravenous administration). Examples of modes of administration which employ a continuous manner of delivery include, but are not limited to, a transdermal patch, a suppository, or a slow release oral formulation.
The word xe2x80x9csubjectxe2x80x9d refers to a patient which is administered the therapeutic composition comprising biologically active vitamin D compounds of the present invention. Examples of subjects, include, but are not limited to, humans and other animals such as non-human primates, horses, dogs, and cats.
The present invention relates to therapeutics for the prevention and treatment of IBD. Specifically, the present invention contemplates the prevention and treatment of IBD in humans as well as other animals through the use of biologically active vitamin D compounds.
The present invention provides a method of treatment, comprising; providing a subject and a therapeutic composition comprising a biologically active vitamin D compound; and administering the therapeutic composition to the subject. It is not intended that the present invention be limited to any particular subject. Indeed, a variety of subjects are contemplated. In one embodiment, the subject is a mammal. In a further embodiment, the subject is a mammal selected from the group of a human, horse, non-human primate, dog, and cat. In a preferred embodiment, the subject is a human. In an additional embodiment, the subject is on a low calcium diet.
In one embodiment, the subject is suffering from symptoms of inflammatory bowel disease. In another embodiment, the subject is suffering from ulcerative colitis. In a different embodiment, the subject is suffering from Crohn""s disease. In a preferred embodiment, the administration of a therapeutic composition comprising a biologically active vitamin D compound reduces the symptoms of disease (i.e. reduces the symptoms of inflammatory bowel disease, ulcerative colitis, or Crohn""s disease). In another embodiment, the biologically active vitamin D compounds are administered under conditions such that the symptoms of IBD are reduced. In a different embodiment, the subject is at risk for inflammatory bowel disease, and the therapeutic composition is administered prophylactically. In still further embodiments, a therapeutically effective amount of a biologically active vitamin D compound is administered to the subject.
It is not intended that the present invention be limited to particular biologically active vitamin D compounds. A variety of biologically active vitamin D compounds are contemplated. In one embodiment, the biologically active vitamin D compound is selected from vitamin D, 1,25 dihydroxyvitamin D3, 1xcex1hydroxyvitamin D3, 1,25-dihydroxyvitamin D2, 1xcex1-hydroxyvitamin D2, 1xcex1,25-(OH)2-16-ene-D3, 1xcex1,25-(OH)2-24-oxo-16-ene-D3, 1xcex1,24R(OH)2-D3, 1xcex1,25(OH)2-22-oxa-D3, 20-epi-22-oxa-24a,24b,-dihomo-1xcex1,25(OH)2-D3, 20-epi-22-oxa-24a,26a,27a,-trihomo-1xcex1,25(OH)2-D320-epi-22-oxa-24homo-1xcex1,25(OH)2-D3, 1,25-(OH)2-16,23E-diene-26-trifluoro-19nor-D3. In a preferred embodiment, the biologically active vitamin D compound is selected from 1,25-dihydroxyvitamin D3, 19-nor-1,25-dihydroxyvitamin D2, 19-nor-1,25-dihydroxy-21-epi-vitamin D3, 1,25-dihydroxy-24-homo-22-dehydro-22E-vitamin D3, and 19-nor-1,25-dihydroxy-24-homo-22-dehydro-22E-vitamin D3, and nonsecosteroidal vitamin D mimics. In a particularly preferred embodiment, the biologically active compound is 1,25-dihydroxyvitamin D3. In an additional embodiment, the biologically active vitamin D compound is selected from the analogs represented by the following formula: 
wherein X1 and X2 are each selected from the group consisting of hydrogen and acyl;
wherein Y1 and Y2 can be H, or one can be O-aryl or O-alkyl while the other is hydrogen and can have a xcex2 or xcex1 configuration; Z1 and Z2 are both H, or Z1 and Z2 taken together are CH2; and
wherein R is an alkyl, hydroxyalkyl or fluoroalkyl group, or R may represent the following side chain: 
wherein (a) may have an S or R configuration and wherein R1 represents hydrogen, hydroxy or O-acyl, R2 and R3 are each selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the groupxe2x80x94(CH2)mxe2x80x94where m is an integer having a value of from 2 to 5, R4 is selected from the group consisting of hydrogen, hydroxy, fluorine, O-acyl, alkyl, hydroxyalkyl and fluoroalkyl, R5 is selected from the group consisting of hydrogen, hydroxy, fluorine, alkyl, hydroxyalkyl and fluoroalkyl, or, R4 and R5 taken together represent double-bonded oxygen, R6 and R7 taken together form a carbonxe2x80x94carbon double bond and R8 may be H or CH3, and wherein n is an integer having a value of from 1 to 5, and wherein the carbon at any one of positions 20, 22, or 23 in the side chain may be replaced by an O, S, or N atom.
In one embodiment, the biologically active vitamin D compounds of the present invention do not cause symptoms of hypercalcemia when administered to a subject. In another preferred embodiment of the present invention, the biologically active vitamin D compounds of the present invention do not generate as much (i.e. a lesser degree) of a calcemic response as compared to calcitriol when administered to a subject. In one embodiment, the biologically active vitamin D compounds have low calcemic response characteristics, inhibit cell proliferation and promote cell differentiation as compared to calcitriol. In another embodiment, these compounds are selected from 1xcex1,25-(OH)2-24-epi-D2, 1xcex1,25-(OH)2-24a-Homo-D3, 1xcex1, 25-(OH)2-24a-Dihomo-D3, 1xcex1,25-(OH)2-19-nor-D3, and 20-epi-24-homo-1xcex1,25-(OH)2-D3.
The present invention also contemplates the administration of a therapeutic composition comprising more than one of the biologically active compounds of the present invention. In other embodiments, the biologically active compounds of the present invention are administered in therapeutically effective amounts. In one embodiment, a preferred dose of the biologically active vitamin D compound for the present invention is the maximum that a patient can tolerate and not develop serious hypercalcemia. In another embodiment, if the biologically active vitamin D compound is not a 1xcex1-hydroxy compound, a daily dose between 1.0 and 100 xcexcg per day per 160 pound patient is administered, while a particularly advantageous daily dose is between 5.0 and 50 xcexcg per day per 160 pound patient. In a different embodiment, if the biologically active vitamin D compound is a 1xcex1-hydroxy compound, a daily dose of between 0.1 and 20 xcexcg per day per 160 pound patient is administered, while a preferred dose is between 0.5 and 10 xcexcg per day per 160 pound patient. In a particularly preferred embodiment, the dose is between 3-10 xcexcg per day. In an additional embodiment, the therapeutic administration of the biologically active vitamin D compounds does not cause serious hypercalcemia. In another embodiment, the therapeutic administration of the biologically active vitamin D compounds only causes mild hypercalcemia. In another embodiment, the biologically active vitamin D compounds do not cause symptoms of hypercalcemia.
It is not intended that the present invention be limited to a particular mode of administration. A variety of modes of administration are contemplated, including intravenously, intramuscularly, subcutaneously, intradermally, intraperitoneally, intrapleurally, intrathecally, orally, rectally and topically. In certain embodiments, the therapeutic compositions are administered via suppository, or in tablet or capsule formulations for oral delivery. In one embodiment, administration of the therapeutic compositions occurs at night. In another embodiment, multiple doses (e.g. 3 or 4) are provided in a 24 hour period. In a further embodiment, the administration of the therapeutic composition is by pulse intravenous therapy. In a particularly preferred embodiment, the therapeutic compositions are administered via a transdermal patch (skin patch).
The present invention also provides a method of treatment, comprising, providing a subject with symptoms of inflammatory bowel disease and a therapeutic composition comprising a biologically active vitamin D compound, and administering the therapeutic compound to the subject. In one embodiment, the biologically active vitamin D compounds are administered to a patient after the surgical removal of damaged tissue. In a preferred embodiment, the present invention provides a method of treatment, comprising, providing a human patient with symptoms of inflammatory bowel disease, a therapeutic composition comprising a biologically active vitamin D compound, and administering the therapeutic composition to the patient under conditions such that said symptoms are reduced.
The present invention also provides a method of treatment, comprising, providing a subject at risk for inflammatory bowel disease and a therapeutic composition comprising a biologically active vitamin D compound, and prophylactically administering the therapeutic compound to the subject. In a preferred embodiment, the prophylactic administration of the biologically active vitamin D compounds delays the onset of the symptoms of inflammatory bowel disease. In a particularly preferred embodiment, the prophylactic administration of the biologically active vitamin D compounds prevents the onset of one or more symptoms of inflammatory bowel disease (e.g. prevents the onset of abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, dehydration, anemia, or malnutrition, or any combination thereof).
The present invention also provides a composition of matter comprising a transdermal patch, wherein said transdermal patch comprises a therapeutic composition comprising biologically active vitamin D compounds. In one embodiment, the transdermal patch comprises a therapeutically effective amount of a biologically active vitamin D compound. In another embodiment, the transdermal patch further comprises a single polymer. In an additional embodiment, the transdermal patch further comprises multiple polymers. In another embodiment, the transdermal patch further comprises a polyurethane acrylic copolymer. In another embodiment, the transdermal patch further comprises silicone or polyisobutylene or both. In a preferred embodiment, the transdermal patch is worn by a subject at risk for Inflammatory Bowel Disease. In another preferred embodiment, the transdermal patch is worn by a subject with symptoms of Inflammatory Bowel Disease. In another embodiment, the transdermal patch delivers biologically active vitamin D compounds to a subject in a continuous manner under conditions such that Symptoms of IBD are reduced.